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ObjectivesTumour necrosis factor inhibitors (TNFis) have been suggested to slow radiographic progression in patients with ankylosing spondylitis. However, limitations such as variations in disease activity, complex drug administration and short follow-up duration make it difficult to determine the effect of TNFis on radiographic progression. The aim of the study was to investigate whether long-term treatment with TNFis can reduce radiographic progression in patients with ankylosing spondylitis using 18-year longitudinal real-world data.MethodsThis retrospective study was conducted between January 2001 and December 2018 at a single centre. Among the 1280 patients whose electronic medical records were reviewed, data of 595 patients exposed to TNFis at least once were included. Among them, time intervals of TNFi exposure or non-exposure were determined in 338 patients (‘on the TNFis’ or ‘off the TNFis’ intervals, respectively). The difference in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) change rate between ‘on the TNFis’ and ‘off the TNFis’ intervals was investigated.ResultsWe obtained 2364 intervals of 338 patients (1281 ‘on the TNFis’ and 1083 ‘off the TNFis’ intervals). In the marginal structural model for inverse probability of treatment weighting, the change rate of mSASSS significantly decreased with the use of TNFis (β=−0.112, p=0.004), and the adjusted mSASSS changes were 0.848 and 0.960 per year during ‘on the TNFis’ and ‘off the TNFis’ intervals, respectively.ConclusionCompared with treatment without TNFis, treatment with TNFis slowed radiologic progression significantly.

The efficacy of antithrombin (AT) administration in patients with septic shock and disseminated intravascular coagulation (DIC) was uncertain. This study aimed to investigate whether high-dose AT administration improves outcomes in patients with septic shock and DIC. This observational, prospective cohort study included consecutive adult septic shock patients with DIC who showed AT activity

Prosocial acts typically take the form of time- or money-donations. Do third-parties differ in how they evaluate these different kinds of donations? Here, we show that consumers view time-donations as more morally praiseworthy and more diagnostic of moral character than money-donations, even when the resource investment is comparable. This moral preference occurs because consumers perceive time-donations as signaling greater emotional investment in the cause and therefore better moral character; this occurs despite consumers’ (correct) belief that time-donations are typically less effective than money-donations (Study 1). This effect in turn is explained by two mechanisms: People believe that time-donations are costlier even when their objective costs are equated, which happens because people rely on a lay theory associating time with the self (Study 2). The more signaling power of time- donations has downstream implications for interpersonal attractiveness in a dating context (Study 3A), employment decisions (Study 3B), and donor decision-making (Study 3). Moreover, donors who are prompted with an affiliation rather (versus dominance) goal are likelier to favor time-donations (Study 4). However, reframing money-donations in terms of time (e.g., donating a week’s salary) reduced and even reversed these effects (Study 5). These results support theories of prosociality that place reputation-signaling as a key motivator of consumers’ moral behavior. We discuss implications for the charity market and for social movements, such as effective altruism, that seek to maximize the social benefit of consumers’ altruistic acts.

To determine whether diffusion- and perfusion-weighted MRI–based radiomics features can improve prediction of isocitrate dehydrogenase (IDH) mutation and tumor aggressiveness in lower grade gliomas (LGGs) Radiomics features (n = 6472) were extracted from multiparametric MRI including conventional MRI, apparent diffusion coefficient (ADC), and normalized cerebral blood volume, acquired on 127 LGG patients with determined IDH mutation status and grade (WHO II or III). Radiomics models were constructed using machine learning–based feature selection and generalized linear model classifiers. Segmentation stability was calculated between two readers using concordance correlation coefficients (CCCs). Diagnostic performance to predict IDH mutation and tumor grade was compared between the multiparametric and conventional MRI radiomics models using the area under the receiver operating characteristics curve (AUC). The models were tested using a temporally independent validation set (n = 28). The multiparametric MRI radiomics model was optimized with a random forest feature selector, with segmentation stability of a CCC threshold of 0.8. For IDH mutation, multiparametric MR radiomics showed similar performance (AUC 0.795) to the conventional radiomics model (AUC 0.729). In tumor grading, multiparametric model with ADC features showed higher performance (AUC 0.932) than the conventional model (AUC 0.555). The independent validation set showed the same trend with AUCs of 0.747 for IDH prediction and 0.819 for tumor grading with multiparametric MRI radiomics model. Multiparametric MRI radiomics model showed improved diagnostic performance in tumor grading and comparable diagnostic performance in IDH mutation status, with ADC features playing a significant role. • The multiparametric MRI radiomics model was comparable with conventional MRI radiomics model in predicting IDH mutation. • The multiparametric MRI radiomics model outperformed conventional MRI in glioma grading. • Apparent diffusion coefficient played an important role in glioma grading and predicting IDH mutation status using radiomics.

Background and aim The clinical significance of incidental pancreatic cystic lesions (PCLs) remains unclear in those that are not accompanied by worrisome features or high-risk stigmata. We aimed to investigate the natural course of PCLs without any risk features and examine the clinical factors associated with their progression. Methods We conducted a retrospective cohort study of 427 patients with PCLs, which were incidentally detected by computed tomography between January 2003 and December 2012. Progression of PCLs without any risk features and the clinical factors associated with their progression were investigated. The length of time to significant growth was also evaluated. Results Ninety-four (22.0%) of the 427 patients had asymptomatic PCLs that showed significant growth after a median surveillance period of 5.3 years; approximately 27.7% of the patients showed significant size changes in the first 5 years, while the remaining 72.3% showed significant changes after 5 years. The cumulative rate of patients with significant growth was associated with initial cyst size and high body mass index. In the growth group, additional treatments were required for 12 patients, one of whom developed malignancy. Four patients in the stable group underwent additional treatment and showed no malignant change. Conclusions One-fifth of the asymptomatic PCLs significantly increased in size after a long-term follow-up period, which was associated with initial cyst size and obesity. The size of PCLs mostly increased after 5 years; although the malignancy risk of PCLs was low, it was still a concern.

A combination of T2/FLAIR mismatch sign and advanced imaging parameters may improve the determination of molecular subtypes of diffuse lower-grade glioma. We assessed the diagnostic value of adding the apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) to the T2/FLAIR mismatch sign for differentiation of the IDH mutation or 1p/19q codeletion. Preoperative conventional, diffusion-weighted, and dynamic susceptibility contrast imaging were performed on 110 patients with diffuse lower-grade gliomas. The study population was classified into three groups using molecular subtype, namely IDH mutation and 1p/19q codeletion (IDHmut-Codel), IDH wild type (IDHwt) and IDH mutation and no 1p/19q codeletion (IDHmut-Noncodel). T2/FLAIR mismatch sign and the histogram parameters of apparent diffusion coefficient (ADC) and normalised cerebral blood volume (nCBV) values were assessed. A multivariate logistic regression model was constructed to distinguish IDHmut-Noncodel from IDHmut-Codel and IDHwt and from IDHwt, and the performance was compared with that of single parameters using the area under the receiver operating characteristics curve (AUC). Positive visual T2/FLAIR mismatch sign and higher nCBV skewness were significant variables to distinguish IDHmut-Noncodel from the other two groups (AUC, 0.88; 95% CI, 0.81–0.96). A lower ADC10 was a significant variable for distinguishing IDHmut-Noncodel from the IDHwt group (AUC, 0.75; 95% CI, 0.62–0.89). Adding ADC or CBV histogram parameters to T2/FLAIR mismatch sign improved performance in distinguishing IDHmut-Noncodel from the other two groups (AUC 0.882 vs. AUC 0.810) or from IDHwt (AUC 0.923 vs. AUC 0.868). The combination of the T2/FLAIR mismatch sign with ADC or CBV histogram parameters can improve the identification of IDHmut-Noncodel diffuse lower-grade gliomas, which can be easily applied in clinical practice. • The combination of the T2/FLAIR mismatch sign with the ADC or CBV histogram parameters can improve the identification of IDHmut-Noncodel diffuse lower-grade gliomas. • The multivariable model showed a significantly better performance for distinguishing the IDHmut-Noncodel group from other diffuse lower-grade gliomas than the T2/FLAIR mismatch sign alone or any single parameter. • The IDHmut-Noncodel type was associated with intermediate treatment outcomes; therefore, the identification of IDHmut-Noncodel diffuse lower-grade gliomas could be helpful for determining the clinical approach.

Background/objectives Prostate-specific antigen (PSA) screening can be of low value in older adults. Our objective was to quantify the prevalence and variation of low-value PSA screening across the Veterans Health Administration (VA), which has instituted programs to reduce low-value care. Design Retrospective cohort. Setting VA administrative data, 2014 to 2015. Participants National random sample (N = 214 480) of male veterans, aged 75 years or older. Measurements We defined PSA screening in men aged 75 years or older without a history of prostate cancer as low value, per established definitions in Medicare. We calculated screening rates overall and by VA Medical Center (VAMC), adjusting for patient and VAMC-level factors. We characterized variation across VAMCs using the adjusted median odds ratio (OR) and compared the adjusted OR of screening between VAMCs in different deciles of low-value screening rates. In separate sensitivity analyses, we assessed screening in veterans at greatest risk of 1-year mortality and among veterans after excluding those who underwent prostatectomy, had a prior PSA elevation, or had a clinical indication for testing. Results Overall, 37 867 (17.7%) of veterans underwent low-value PSA screening (VAMC range = 3.3%-38.2%). The adjusted median OR was 1.88, meaning the median odds of screening would increase by 88% were a veteran to transfer his care to a VAMC with higher screening rates. Veterans at VAMCs in the top decile had an adjusted OR of 12.9 (95% confidence interval = 11.0-15.2) compared to those veterans in the lowest decile. Among veterans with the greatest mortality risk (n = 23 377), 3496 (15.0%) underwent screening (VAMC range = 1.7%-46.3%). After excluding veterans with a prior prostatectomy, PSA elevation, or a potential clinical indication, 31 556 (14.7%) underwent screening (VAMC range = 2.0%-49.9%). Conclusions In a national cohort of older veterans, more than one in six received low-value PSA screening, with greater than 10-fold variation across VAMCs and high rates of screening among those with the greatest mortality risk. J Am Geriatr Soc 67:1922-1927, 2019.

A tablet film coating and drying process was assessed by an experimentally validated thermodynamic balance model. Mass conservation equations were derived for the process air and the aqueous coating solution. Thermodynamic behavior of the solution was described by evaporation at the tablet surface and penetration into the tablet. Energy balance equations including heat loss to the atmosphere were coupled to the mass conservation equation. Experimental data using the ConsiGma™ coater (GEA, Belgium) were used for both parameter estimation and model validation. The results showed the proposed model can investigate primitive outlet variables and further internal variables representing evaporation and penetration. A sensitivity analysis revealed that evaporation depended more on the input parameters while penetration hinges on the tablet properties, particularly on the tablet volume affecting the tablet porosity.

Prosocial acts often take the form of time- or money-donations. Do third-parties differ in how they evaluate these different kinds of donations? Two studies show that time-donations are viewed as more praiseworthy than money-donations, even when the resource investment is comparable. We provide evidence that this moral preference occurs because time-donations are seen as signaling greater emotional investment in the cause and therefore better moral character. Moreover, time- donations are viewed as more praiseworthy even though people actually believe that they are less effective than money donations. Overall, we take these results to support theories of prosociality that place character- or reputation-signaling at a key motivator of moral behavior. These results have implications for social movements, such as effective altruism, that seek to maximize the social benefit of altruistic acts.

The recent introduction of various high-dimensional modeling methods, such as radiomics and deep learning, has created a much greater diversity in modeling approaches for survival prediction (or, more generally, time-to-event prediction). The newness of the recent modeling approaches and unfamiliarity with the model outputs may confuse some researchers and practitioners about the evaluation of the performance of such models. Methodological literacy to critically appraise the performance evaluation of the models and, ideally, the ability to conduct such an evaluation would be needed for those who want to develop models or apply them in practice. This article intends to provide intuitive, conceptual, and practical explanations of the statistical methods for evaluating the performance of survival prediction models with minimal usage of mathematical descriptions. It covers from conventional to deep learning methods, and emphasis has been placed on recent modeling approaches. This review article includes straightforward explanations of C indices (Harrell's C index, etc.), time-dependent receiver operating characteristic curve analysis, calibration plot, other methods for evaluating the calibration performance, and Brier score.

Most of the commercial devices for vitrification are directly immersed into the warming solution (WS) for increasing of warming rate. However, the previous modified cut standard straw (MCS) which has reported is difficult to immerse into the WS. The aim of this study was to investigate whether the long cut straw (LCS) could be useful as a stable tool for vitrified-warmed human blastocysts. A total of 138 vitrified-warmed cycles were performed between November 2013 and November 2014 (exclusion criteria: women ≥38 years old, poor responder, surgical retrieval sperm, and severe male factor). The artificial shrinkage was conducted using 29-gauge needles. Ethylene glycol and dimethyl sulfoxide (7.5% and 15% (v/v)) were used as cryoprotectants. Freezing and warming were conducted using the LCS tool. The cap of LCS was removed using the forceps in the liquid nitrogen (LN2) and then directly immersed into the first WS for 1 min at 37℃ (1 M sucrose). Only re-expanded blastocysts were transferred after it was cultured in sequential media for 18-20 h. A total of 294 blastocysts were warmed, and all were recovered (100%). Two hundred eighty-five embryos were survived (96.9%). The vitrifiedwarmed blastocysts of all patients were transferred without any cancellation. We were able to achieve a reasonable implantation (24.2%), following by clinical pregnancy (36.2%), which then continued to ongoing pregnancy (36.2%), and live birth (31.2%). Using LCS is achieved the acceptable rates of survival, pregnancy and live birth. Therefore, the LCS could be considered as a stable and simple tool for human embryo vitrificaton.

Broadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5- to 2-log 10 reductions in HIV replication in ectocervical tissues and ≈3-log 10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection.

Background The purpose of this study was to describe the delivery of prenatal care services to women with opioid use disorder (OUD) on opioid maintenance therapy at high risk for hepatitis C virus (HCV) infection. Methods We conducted a retrospective cohort evaluation of 791 pregnant women with OUD from 2009 to 2012. HCV screening was defined as documentation of (a) an anti-HCV antibody test or (b) a provider discussion regarding a known HCV diagnosis during pregnancy. Multivariate logistic regression was used to identify predictors of HCV screening during pregnancy. Results Among 791 pregnant women with OUD, 611 (77.2%) were screened for HCV infection and 369/611 (60.4%) were HCV positive. In multivariable analysis, patients who were married (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.29, 0.91), used buprenorphine (OR = 0.45; 95% CI = 0.28, 0.71), and were cared for by private practice providers (OR = 0.29; 95% CI = 0.19, 0.45) were significantly less likely to be screened. In contrast, patients who used benzodiazepines (OR = 1.72; 95% CI = 1.02, 2.92), intravenous (IV) opioids (OR = 6.15; 95% CI = 3.96, 9.56), had legal problems (OR = 2.23; 95% CI = 1.12, 4.45), had children not in their custody (OR = 1.81; 95% CI = 1.01, 3.24), and who had a partner with substance abuse history (OR = 2.38; 95% CI = 1.23, 4.59) were significantly more likely to be screened. Of 369 HCV-positive patients, a new diagnosis of HCV was made during pregnancy for 108 (29.3%) patients. Only 94 (25.5%) had HCV viral load testing, 61 (16.5%) had HCV genotype testing, and 38 (10.4%) received an immunization for hepatitis A. Although 285 (77.2%) patients were referred to hepatology, only 71 (24.9%) attended the consultation. Finally, only 6 (1.6%) patients received HCV treatment 1 year following delivery. Conclusions Prenatal care approaches to HCV infection remain inconsistent, and the majority of patients diagnosed with HCV infection during pregnancy do not receive treatment after delivery.

We conducted a case-control study of 18 US transplant recipients with Rhodococcus infection and 36 matched controls. The predominant types of infection were pneumonia and bacteremia. Diabetes mellitus and recent opportunistic infection were independently associated with disease. Outcomes were generally favorable except for 1 relapse and 1 death.

We thank Zhang et al 1 for their interest in our study, titled “Tumour necrosis factor inhibitors slow radiographic progression in patients with ankylosing spondylitis: 18-year real-world evidence.” We investigated long-term observational data using advanced statistical methods to determine whether changes in radiographic progression are affected by tumour necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS).2 However, our study did not consider the risk of osteoporosis or vertebral fractures while evaluating the effects of TNFi. There are several studies on bone mineral density (BMD) in patients with AS. Compared with the general population, patients with AS have a lower BMD.3–5 …

We developed a stand-alone, real-time optical detection device capable of reading fluorescence intensities from cell samples with high sensitivity and precision, for use as a portable fluorescent sensor for sensing fluorescently labeled enterohemorrhagic Escherichia coli (EHEC) Shiga toxins (Stxs). In general, the signal intensity from the fluorescently labeled Stxs was weak due to the small number of molecules bound to each cell. To address this technical challenge, we used a highly sensitive light detector (photomultiplier tube: PMT) to measure fluorescence, and designed a portable optical housing to align optical parts precisely; the housing itself was fabricated on a 3D printer. In addition, an electric circuit that amplified PMT output was designed and integrated into the system. The system shows the toxin concentration in the sample on a liquid crystal display (LCD), and a microcontroller circuit is used to read PMT output, process data, and display results. In contrast to other portable fluorescent detectors, the system works alone, without any peripheral computer or additional apparatus; its total size is about 17 × 13 × 9 cm3, and it weighs about 770 g. The detection limit was 0.01 ppm of Alexa Fluor 488 in PBS, which is ten thousand times lower than those of other smartphone-based systems and sufficiently sensitive for use with a portable optical detector. We used the portable real-time optical sensing system to detect Alexa Fluor 488-tagged Stx2B-subunits bound to monocytic THP-1 cells expressing the toxin receptor globotriaosylceramide (Gb3). The device did not detect a signal from Gb3-negative PD36 cells, indicating that it was capable of specifically detecting Stxs bound to cells expressing the toxin receptor. Following the development of a rapid and autonomous method for fluorescently tagging cells in food samples, the optical detection system described here could be used for direct detection of Shiga toxins in food in the field.

Background: Few studies have compared perioperative and oncological outcomes between minimally invasive pancreatoduodenectomy (MIPD) and open pancreatoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDAC). Methods: A retrospective review of patients undergoing MIPD and OPD for PDAC from January 2011 to December 2017 was performed. Perioperative, oncological, and survival outcomes were analyzed before and after propensity score matching (PSM). Results: Data from 1048 patients were evaluated (76 MIPD, 972 OPD). After PSM, 73 patients undergoing MIPD were matched with 219 patients undergoing OPD. Operation times were longer for MIPD than OPD (392 vs. 327 min, p &lt, 0.001). Postoperative hospital stays were shorter for MIPD patients than OPD patients (12.4 vs. 14.2 days, p = 0.040). The rate of overall complications and postoperative pancreatic fistula did not differ between the two groups. Adjuvant treatment rates were higher following MIPD (80.8% vs. 59.8%, p = 0.002). With the exception of perineural invasion, no differences were seen between the two groups in pathological outcomes. The median overall survival and disease-free survival rates did not differ between the groups. Conclusions: MIPD showed shorter postoperative hospital stays and comparable perioperative and oncological outcomes to OPD for selected PDAC patients. Future randomized studies will be required to validate these findings.

Sulfonylurea-receptor-1(SUR1) and its associated transient-receptor-potential cation channel subfamily-M (TRPM4) channel are key contributors to cerebral edema and intracranial hypertension in traumatic brain injury (TBI) and other neurological disorders. Channel inhibition by glyburide is clinically promising. ABCC8 (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial pressure (ICP). This project evaluated whether TRPM4 SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe TBI patients. Without a priori selection, all 11 TRPM4 SNPs available on the multiplex platform (Illumina:Human-Core-Exome v1.0) were genotyped spanning the 25 exon gene. A total of 385 patients were analyzed after quality control. Outcomes included ICP and 6 month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modeling, and functional predictions were determined using established software programs. rs8104571 (intron-20) and rs150391806 (exon-24) were predictors of ICP. rs8104571 heterozygotes predicted higher average ICP (β = 10.3 mm Hg, p = 0.00000029), peak ICP (β = 19.6 mm Hg, p = 0.0007), and proportion ICP >25 mm Hg (β = 0.16 p = 0.004). rs150391806 heterozygotes had higher mean (β = 7.2 mm Hg, p = 0.042) and peak (β = 28.9 mm Hg, p = 0.0015) ICPs. rs8104571, rs150391806, and 34 associated proxy SNPs in linkage-disequilibrium clustered downstream. This region encodes TRPM4's channel pore and a region postulated to juxtapose SUR1 sequences encoded by an ABCC8 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive ABCC8 SNPs (rs2237982, rs2283261, rs11024286). Although not significant in univariable or a basic multivariable model, in an expanded model additionally accounting for injury pattern, computed tomographic (CT) appearance, and intracranial hypertension, heterozygous rs8104571 was associated with favorable 6 month GOS (odds ratio [OR] = 16.7, p = 0.007951). This trend persisted in a survivor-only subcohort (OR = 20.67, p = 0.0168). In this cohort, two TRPM4 SNPs predicted increased ICP with large effect sizes. Both clustered downstream, spanning a region encoding the channel pore and interacting with SUR1. If validated, this may guide risk stratification and eventually inform treatment-responder classification for SUR1-TRPM4 inhibition in TBI. Larger studies are warranted.

Purpose: Survival rates after non-shockable out-of-hospital cardiac arrest (OHCA) remain low despite advances in resuscitation. Cardiopulmonary resuscitation (CPR) process measures may inform treatment strategies. We hypothesized that CPR process measures would be associated with return of spontaneous circulation (ROSC) and patient electrocardiogram (ECG) transitions. Methods: We obtained defibrillator monitor data for emergency medical service (EMS)-treated non-shockable OHCA from the Resuscitation Outcomes Consortium (ROC), an OHCA research network (U.S./Canada). We extracted ECG data from EMS defibrillator files and parsed cases into compression-free analyzable segments using custom MATLAB software. Two data abstractors classified segment rhythms as PEA, asystole, ventricular fibrillation (VF), pulseless ventricular tachycardia (PVT), or ROSC. We calculated CPR process measures (average rate, depth, duration, leaning proportion, chest compression fraction, and duty cycle) for CPR bouts preceding every ECG segment. We used mixed effects models controlling for subject to test associations between individual CPR process measures and the bout-level outcomes ROSC and shockable rhythm. Results: We analyzed 1893 cases consisting of 7981 CPR bouts. Case initial rhythms were asystole (68.2%), PEA (24.9%), or NSA-AED (6.9%). Segment rhythm classifications were asystole (78.1%), PEA (20.4%), ROSC (5.5%), VF (1.4%), and PVT (0.07%). Regression model results are shown in Table 1. Chest compression fraction was most strongly associated with ROSC and shockable rhythm. Depth was also associated with shockable rhythm. Leaning proportion and duty cycle were not associated with either outcome. Conclusions: In cases of non-shockable OHCA, CPR quality measures were associated with ROSC and transition to a shockable rhythm at the bout level.

Intracranial pressure in traumatic brain injury is dynamic and influenced by factors like injury patterns, treatments, and genetics. Existing studies use time invariant summary intracranial pressure measures thus potentially losing critical information about temporal trends. We identified longitudinal intracranial pressure trajectories in severe traumatic brain injury and evaluated whether they predicted outcome. We further interrogated the model to explore whether ABCC8 polymorphisms (a known cerebraledema regulator) differed across trajectory groups.Prospective observational cohort.Single-center academic medical center.Four-hundred four severe traumatic brain injury patients.None.We used group-based trajectory modeling to identify hourly intracranial pressure trajectories in days 0-5 post traumatic brain injury incorporating risk factor adjustment (age, sex, Glasgow Coma Scale 6score, craniectomy, primary hemorrhage pattern). We compared 6-month outcomes (Glasgow Outcome Scale, Disability Rating Scale, mortality) and ABCC8 tag-single-nucleotide polymorphisms associated with cerebral edema (rs2237982, rs7105832) across groups. Regression models determined whether trajectory groups predicted outcome. A six trajectory group model best fit the data, identifying cohorts differing in initial intracranial pressure, evolution, and number/proportion of spikes greater than 20 mm Hg. There were pattern differences in age, hemorrhage type, and craniectomy rates. ABCC8 polymorphisms differed across groups. GOS (p = 0.006), Disability Rating Scale (p = 0.001), mortality (p0.0001), and rs2237982 (p = 0.035) differed across groups. Unfavorable outcomes were surprisingly predicted by both low intracranial pressure trajectories and sustained intracranial hypertension. Intracranial pressure variability differed across groups (p0.001) and may reflect preserved/impaired intracranial elastance/compliance.We employed a novel approach investigating longitudinal/dynamic intracranial pressure patterns in traumatic brain injury. In a risk adjusted model, six groups were identified and predicted outcomes. If validated, trajectory modeling may be a first step toward developing a new, granular approach for intracranial pressure phenotyping in conjunction with other phenotyping tools like biomarkers and neuroimaging. This may be particularly relevant in light of changing traumatic brain injury demographics toward the elderly.

To characterize geographic variability of generic benign prostatic hyperplasia (BPH) medications in order to improve drug price transparency and improve patient access to affordable medication sources. This is of interest because BPH is one of the most common chronic diseases in men and contributes to individual healthcare cost. Medical therapy is the main treatment modality for BPH, burdening patients with lifelong medication expenses which may impact adherence and subsequent outcomes. With an aging population, this is compounded by many older individuals requiring multiple daily medications.All pharmacies within a 25-mile radius of our institution were identified and classified as chain, wholesale or independent. The out-of-pocket price for a 30-day supply of tamsulosin (0.4 mg), finasteride (5 mg), oxybutynin (5 mg TID), and oxybutynin 10 mg XL were obtained using a scripted telephone survey. Multivariable linear regression assessed the association between census-tract level demographic and socioeconomic factors and disparate generic out-of-pocket drug-pricing.The response rate was 93% with 255 pharmacies across 173 census tracts providing data. By pharmacy type, there was up to 5.5-fold variation in median out-of-pocket drug prices for the most common BPH medications. Demographic and socioeconomic factors were not significantly associated with generic BPH drug price variation.The out-of-pocket price of generic medications for BPH varies significantly between pharmacies in a geographically-confined area. This study highlights the need for quality improvement initiatives that empower patients to price-compare and improve drug price transparency.

Cerebral edema is critical to morbidity/mortality in traumatic brain injury (TBI) and is worsened by hypotension. Glibenclamide may reduce cerebral edema by inhibiting sulfonylurea receptor-1 (Sur1); its effect on diffuse cerebral edema exacerbated by hypotension/resuscitation is unknown. We aimed to determine if glibenclamide improves pericontusional and/or diffuse edema in controlled cortical impact (CCI) (5m/sec, 1 mm depth) plus hemorrhagic shock (HS) (35 min), and compare its effects in CCI alone. C57BL/6 mice were divided into five groups (n = 10/group): naïve, CCI+vehicle, CCI+glibenclamide, CCI+HS+vehicle, and CCI+HS+glibenclamide. Intravenous glibenclamide (10 min post-injury) was followed by a subcutaneous infusion for 24 h. Brain edema in injured and contralateral hemispheres was subsequently quantified (wet-dry weight). This protocol brain water (BW) = 80.4% vehicle vs. 78.3% naïve, p

Hepatocellular carcinoma (HCC) can result from hepatitis B or C infection, fibrosis or cirrhosis. Transforming growth factor-β (TGF-β) is one of the main growth factors associated with fibrosis or cirrhosis progression in the liver, but its role is controversial in hepatocarcinogenesis. In the present study, the effect of TGF-β on the HCC Huh-7 and Huh-Bat cell lines was evaluated. To study the effect of TGF-β, Huh-7 and Huh-Bat cells were treated with TGF-β and a TGF-β receptor inhibitor (SB431542). Cell survival, cell cycle, numbers of side population (SP) cells and expression of the cancer stem cell marker cluster of differentiation (CD)133, epithelial-mesenchymal transition markers (E-cadherin, α-smooth muscle actin and vimentin) and TGF-β-regulated proteins [phospho-c-Jun N-terminal kinase (p-JNK), p-c-Jun and p-smad2] were investigated. TGF-β treatment resulted in decreased cell survival with a targeted effect on SP cells. Expression of CD133 and vimentin was upregulated by treatment with the TGF-β receptor antagonist SB431542, but not with TGF-β. By contrast, TGF-β induced accumulation of cells at G0/G1, and upregulated expression of p-JNK, p-c-Jun and p-smad2. However, these effects were blocked when cells were treated with TGF-β plus SB431542, indicating the specificity of the TGF-β effect. The present results indicated that TGF-β has anticancer effects mediated by survival inhibition of cancer stem cells, which may be developed as a novel therapy for HCC.

Continuous manufacturing techniques are increasingly being adopted in the pharmaceutical industry and powder blending is a key operation for solid-dosage tablets. A modeling methodology involving axial and radial tanks-in-series flowsheet models is developed to describe the residence time distribution (RTD) and blend uniformity of a commercial powder blending system. Process data for a six-component formulation processed in a continuous direct compression line (GEA Pharma Systems) is used to test the methodology. Impulse tests were used to generate experimental RTDs which are used along with parameter estimation to determine the number of axial tanks in the flowsheet. The weighted residual from the parameter estimation was less than the χ

Objective This study aims to identify risk factors for cesarean delivery (CD) surgical site infection (SSI). Study Design Retrospective analysis of 2,739 CDs performed at the University of Pittsburgh in 2011. CD SSIs were defined using National Healthcare Safety Network (NHSN) criteria. Chi-square test and t-test were used for bivariate analyses and multivariate logistic regression was used to identify SSI risk factors. Results Of 2,739 CDs, 178 (6.5%) were complicated by SSI. Patients with a SSI were more likely to have Medicaid, have resident physicians perform the CD, an American Society of Anesthesiologists (ASA) class of ≥ 3, chorioamnionitis, tobacco use, and labor before CD. In multivariable analysis, labor (odds ratio [OR], 2.35; 95% confidence interval [95% CI], 1.65–3.38), chorioamnionitis (OR, 2.24; 95% CI, 1.25–3.83), resident teaching service (OR, 2.15; 95% CI, 1.54–3.00), tobacco use (OR, 1.70; 95% CI, 1.04–2.70), ASA class ≥ 3 (OR, 1.61; 95% CI, 1.06–2.39), and CDs performed for nonreassuring fetal status (OR, 0.43; 95% CI, 0.26–0.67) were significantly associated with CD SSI. Conclusion Multiple patient, provider, and procedure-specific risk factors contribute to CD SSI risk which may be targeted in infection-control efforts.

Allosensitized children who require a negative prospective crossmatch have a high risk of death awaiting heart transplantation. Accepting the first suitable organ offer, regardless of the possibility of a positive crossmatch, would improve waitlist outcomes but it is unclear whether it would result in improved survival at all times after listing, including posttransplant. We created a Markov decision model to compare survival after listing with a requirement for a negative prospective donor cell crossmatch (WAIT) versus acceptance of the first suitable offer (TAKE). Model parameters were derived from registry data on status 1A (highest urgency) pediatric heart transplant listings. We assumed no possibility of a positive crossmatch in the WAIT strategy and a base-case probability of a positive crossmatch in the TAKE strategy of 47%, as estimated from cohort data. Under base-case assumptions, TAKE showed an incremental survival benefit of 1.4 years over WAIT. In multiple sensitivity analyses, including variation of the probability of a positive crossmatch from 10% to 100%, TAKE was consistently favored. While model input data were less well suited to comparing survival when awaiting transplantation across a negative virtual crossmatch, our analysis suggests that taking the first suitable organ offer under these circumstances is also favored.

Little is known about whether or not a consistently high level of homework adherence over the course of therapy benefits patients. This question was examined in two samples of patients who were receiving individual Cognitive Behavioral Therapy (CBT) for depression (Ns = 128 [Sequenced Treatment Alternatives to Relieve Depression: STAR-D] and 183 [Continuation Phase Cognitive Therapy Relapse Prevention: C-CT-RP]). Logistic and linear regression and propensity score models were used to identify whether or not clinician assessments of homework adherence differentiated symptom reduction and remission, as assessed by the Hamilton Depression Rating Scale-17 (HDRS-17), the Quick Inventory of Depressive Symptomatology-Self-Reported Scale (QIDS-SR), and the QIDS-Clinician Scale (QIDS-C). CBT-related response and remission were equally likely between both high and low homework adherers in both studies and in all models. But in propensity adjusted models that adjusted for session attendance, for both the STAR-D and C-CT-RP samples, greater homework adherence was significantly associated with greater response and remission from depression in the first and last 8 sessions of CBT. Our results suggest that homework adherence can account for response and remission early and late in treatment, with adequate session attendence.

Liver cancer is one of the most drug-resistant cancer types, and cancer stem cells are related to drug resistance. c-Jun-N-terminal kinase (JNK) signaling is involved in drug resistance, and the side population of cells (SP cells) can be used as a model to study liver cancer stem cells. We sought to evaluate the relationship between SP cells and JNK signaling in hepatocarcinoma cells. For this purpose, we examined cell proliferation and the SP cell ratio following treatment of Huh7 cells with the anticancer drugs 5-fluorouracil (5-FU) and paclitaxel. The expression of phospho-stress-activated protein kinase (SAPK)/JNK in the treated cells was evaluated using immunoblotting. 5-FU and paclitaxel treatment increased the number of SP cells and JNK phosphorylation, and decreased cell survival. Huh7 and HepG2 cells were also treated with SP600125, a JNK inhibitor, to study the relationship between SP cells and JNK signaling. The increase in the number of SP cells and the SAPK/JNK and c-Jun phosphorylation was reverted by SP600125 treatment in these cells. We also used immunohistochemistry and showed that SAPK/JNK and c-Jun phosphorylation are increased in hepatocarcinoma tissues. In conclusion, our results demonstrate that the number of SP cells and SAPK/JNK phosphorylation are increased upon treatment with anticancer drugs, and that this increase is blocked by inhibition of JNK signaling. These findings suggest that drug resistance in liver cancer may involve an increase in the number of SP cells following JNK activation.

It is not known whether unmet palliative care needs are associated with an interest in palliative care services among patients with advanced cancer receiving ongoing oncology care.To assess the association between unmet palliative care needs and patient interest in subspecialty palliative care services.Cross-sectional telephone survey.One hundred sixty-nine patients with advanced cancer receiving care from 20 oncologists at two academic cancer centers.Surveys assessed palliative care needs in six domains. Patients were read a description of palliative care and then asked three questions about their current interest in subspecialty palliative care services (perceived need, likelihood of requesting, willingness to see if their oncologist recommended; all outcomes on 0-10 Likert scale).The vast majority of patients described unmet palliative care needs, most commonly related to psychological/emotional distress (62%) and symptoms (62%). In fully adjusted models accounting for clustering by oncologist, unmet needs in these domains were associated with a higher perceived need for subspecialty palliative care services (psychological/emotional needs odds ratio [OR] 1.30; 95% confidence interval [CI] 1.06-1.58; p=0.01; symptom needs OR 1.27; 95% CI 1.01-1.60; p=0.04). There was no significant association between unmet needs and likelihood of requesting palliative care services. Willingness to see palliative care if oncologist recommended was high (mean 8.6/10, standard deviation [SD] 2).Patients with advanced cancer and unmet symptom and psychological/emotional needs perceive a high need for subspecialty palliative care services but may not request them. Efforts to increase appropriate use of subspecialty palliative care for cancer may require oncologist-initiated referrals.

The natural microorganism Escherichia coli without modification is not suitable for the efficient production of 2,3-butanediol (2,3-BD) on an industrial scale because of its poor metabolic performance. Metabolic capacities of E. coli have been improved to produce 2,3-BD efficiently, the performance of which is possible for producing such a product. Codon optimization with the ribosome-binding site for the efficient production of target genes (budA and budC) was achieved by molecular engineering, which allowed the metabolic engineering to proceed to the next level. As a result, comparing the productivity in 26 H, where the amount of p18COR was 1.04 g/L and that of p18WTR was 0.41 g/L, represents an approximate 60.6% increase in the productivity of the p18WTR with codon optimization. In other words, p18COR was 2.54-fold greater than p18WTR in the production of 2,3-BD.

Background Commensal gut bacteria are thought to protect against C. difficile infection (CDI) by producing metabolites that inhibit C. difficile germination and growth. Alternatively, the protective effect could reflect nutrient competition or other mechanisms of chemical communication that also involve the host. CDI treatment using a broad-spectrum antibiotic such as vancomycin (VAN) dramatically depletes commensal bacteria. This dysbiosis can persist for several weeks after end-of-therapy (EOT), and is associated with increased recurrence risk. In this study, we investigate the hypothesis that treating CDI with a more selective antibiotic reduces collateral damage to the intestinal microbiota, preserving or restoring a CDI-inhibitory metabolic profile. Methods Stool samples were collected from CDI patients treated with either a narrow- (RDZ) or broad-spectrum antibiotic (VAN) at days 1, 10 (EOT), 25, and 40. Global metabolite profiles were measured by untargeted LC-MS. Results Untargeted metabolite analysis showed broad differences in the metabolic activity of intestinal microbiota of RDZ- and VAN-treated subjects (Figure 1). At EOT, 28% of LC-MS features detected in both RDZ and VAN samples were differentially present (FDR corrected P-value Conclusion Our data suggest that RDZ treatment correlates with enhanced preservation of bacteria-derived ligands regulating intestinal immune function and substrates of bacterial metabolism. These metabolic profile differences between a narrow- and broad-spectrum antibiotic may contribute to their varying efficacy in preventing CDI recurrence. Disclosures All authors: No reported disclosures.

The original version of this article unfortunately contained a mistake. The name of Chin-Sung Chang was presented incorrectly. The corrected author list is given above.

Aim Side population (SP) cells are known to be enriched in stem/progenitor-like cells. Transforming growth factor (TGF)-β signaling is associated with extracellular matrix (ECM) production in hepatic stellate cells. We hypothesized that the SP fraction in LX2 cells is associated with ECM deposition, which is regulated through TGF-β signaling. Methods We investigated the relationship between SP cells and TGF-β signaling in the hepatic stellate cell line LX2. The effects of TGF-β and SB431542 on the SP fraction and expression of collagen type I and phospho-Smad2 was determined. Results We identified 0.8–3% SP cells in LX2 cells. The growth rate of sorted SP and non-SP cells was similar to that of the original LX2 population, but population of the G0/G1 phase was increased in SP cells. Treatment of LX2 cells with TGF-β decreased the SP fraction in a dose-dependent manner and increased the production of collagen type I. Treatment of LX2 cells with SB431542 blocked the effect of TGF-β on the SP fraction and the expression of collagen type I. We cultured LX2 cells on collagen-coated dishes to observe the effect of ECM deposition on the SP fraction. The growth rate and cell cycle distribution was similar to that observed on normal tissue culture dishes, but the SP fraction was decreased when LX2 cells were cultured on collagen-coated plates. Conclusion These results show that LX2 cells contain an SP fraction and that TGF-β signaling is involved in the induction of ECM deposition as well as the number of SP cells.

Allosensitization is associated with inferior waitlist outcomes in pediatric heart transplant candidates, presumably because of the requirement for a negative prospective crossmatch. However, there are no reports of heart transplant candidate outcomes according to prospective crossmatch requirements.We analyzed data on all children listed for isolated heart transplantation from 1995 to 2009 in the USA according to prospective crossmatch requirement (PXMR). Primary objectives were to describe the prevalence of PXMR at and during listing and to compare waitlist and post-transplant survival for patients based on PXMR. Patients with a PXMR during listing include those with a PXMR at the time of listing as well as those who were designated by the listing center as needing a prospective crossmatch at some point after being placed onto the waitlist.Among 6,343 listed children, 7.7% had a requirement for a prospective crossmatch at the time of listing and 11.8% had a requirement for a prospective crossmatch during listing. After controlling for risk factors associated with inferior survival, PXMR at listing was associated with increased waitlist mortality (HR 1.32, 95% CI 1.10 to 1.56; p = 0.003). Recipients with a PXMR during listing more commonly had a positive DSXM (22.1% vs 10.3%, p0.0001), as did recipients who carried a PXMR throughout listing (21.7% vs 11.3%, p = 0.004). However, there was no significant difference in post-transplant survival on the basis of a PXMR during listing (HR 1.04, 95% CI 0.87 to 1.25; p = 0.67). Nearly 30% of recipients with a PXMR during listing had a peak pre-transplant PRA ≤ 10%.PXMR increases the likelihood of death while awaiting, but not after, pediatric heart transplantation. Further study is necessary to understand how PXMR is applied, and changes, after listing for pediatric heart transplantation.

Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE. DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004). This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.